title: Establishing a reference group for distal 18q-: clinical description and molecular basis.
abstract: Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified 16 individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.6-Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA, cody@uthscsa.edu.
authors.forename: Jannine D
authors.initials: JD
authors.lastname: Cody
authors.forename: Minire
authors.initials: M
authors.lastname: Hasi
authors.forename: Bridgette
authors.initials: B
authors.lastname: Soileau
authors.forename: Patricia
authors.initials: P
authors.lastname: Heard
authors.forename: Erika
authors.initials: E
authors.lastname: Carter
authors.forename: Courtney
authors.initials: C
authors.lastname: Sebold
authors.forename: Louise
authors.initials: L
authors.lastname: O'Donnell
authors.forename: Brian
authors.initials: B
authors.lastname: Perry
authors.forename: Robert F
authors.initials: RF
authors.lastname: Stratton
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Hale
mesh_terms: D000223:Adaptation, Psychological; D000293:Adolescent; D000328:Adult; D020817:Asperger Syndrome / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D007621:Karyotyping; D008137:Longitudinal Studies; D008297:Male; D010641:Phenotype; D015843:Serpins / Q000235:genetics*; D013781:Texas; D055815:Young Adult
chemical_list: C121291:CDH7 protein, human; D015820:Cadherins; C108403:SERPINB8 protein, human; D015843:Serpins